Actinic keratosis (AK) is the most common precancerous lesion - manifesting as thickened scaly or crusty patches of skin - in humans, and its treatment represents a common reason for patients to see a dermatologist. Recent studies estimate that there are approximately 58 million AKs in the US population leading to 5.2 million office visits per year with an approximate cost of 0.9-1.2 billion dollars. The risk for developing an AK is directly related to the degree of photodamage which is a function of age, sun exposure, and Fitzpatrick-skin type (being more common in fair-skinned people). Studies show that multiple AKs significantly decrease the quality of life in patients, leading some investigators to use the term ‘actinic neoplasia syndrome’ for such patients. Some of these pre-cancers progress to squamous cell carcinoma (cSCC), which is discussed below.
Current AK treatments involve topical and destructive modalities. AKs can be treated by freezing the skin with liquid nitrogen (N2). Although technically simple, this therapy has adverse effects which include dyspigmentation, pain, stinging, and a low efficacy rate; liquid N2 is associated with only an 83% clearance rate and lacks specificity for lesional cells requiring the freezing of at least 1 mm of surrounding non-lesional tissue. Other commonly used destructive therapies include: curettage and surgical excision. Since patients often have many AKs requiring treatment; this limits the use of destructive modalities because of the cosmetic deficits associated with dyspigmentation and scarring.
The primary topical agents to treat AKs are 5-fluorouracil (5-FU), imiquimod (ALDARA®), and diclofenac (e.g., SOLARAZE®) 5-FU is a chemotherapeutic agent that inhibits RNA and DNA synthesis and targets dividing cells which are more prevalent in AKs than adjacent epidermis. 5-FU is used as 0.5%, 2.5%, or 5.0% formulations which correspond to compound concentrations of (36-360 mM). 5-FU has significant side effects including prominent inflammation, ulceration, and even scarring; given these side-effects, topical 5-FU is associated with a lower quality of life for patients. Imiquimod, a Toll receptor 7 agonist, produces prominent inflammation to eliminate AKs. The prominent inflammation stimulated by imiquimod is irritating and mimics psoriasis, and this reaction has been associated with autoimmune reactions such as alopecia areata and vitiligo. Another common topical agent to treat AKs is diclofenac, a topical non-steroidal anti-inflammatory compound with an unclear mechanism of action on actinic keratoses. Recent studies using diclofenac and imiquimod showed therapeutic weaknesses associated with poor clearance rates and significant irritation.
Overall, the most commonly used topical agents to treat AKs have significant negative features including irritation, decreased quality of life, and limited efficacy. cSCC is the second most common form of cancer with an annual incidence of 620,000 cases annually. According to some studies, cSCCs cause approximately 8,000 cases of nodal metastasis leading to 3,000 deaths in the US alone each year. In 2004, the estimated cost of treating cSCCs in the US alone was approximately 500 million dollars. The risk factors for cSCCs are similar to those for AKs and include age, male sex, and cumulative UV exposure from sunlight or tanning salons. Since Americans are living longer, spending more time outdoors, and not adequately using sunscreens, it is likely that the numbers of cSCCs in the United States will increase, as will the cost to treat them.
Accordingly, there exists a need for improved therapy modalities and compositions to treat pre-cancerous skin lesions, skin tumors, and their associated diseases or disorders.